Infectious Diarrhea in Children: Working Group Report of the First World Congress of Pediatric Gastroenterology, Hepatology, and Nutrition

I. SUMMARY OF THE PROBLEM Infectious diarrhea remains a major cause of mortality in developing countries, and despite the intervention of proper sanitation and clean water, it is also a major cause of morbidity and hospitalization in developed countries. This is also in the face of the existence of a safe, well-documented, and effective approach to management that has been widely promulgated by prestigious national and international academic bodies (1). Definition of Acute Diarrhea Diarrhea can be defined by measured stool volume (greater than 10 mL/kg/d), but from the clinical setting a more appropriate definition is the passage of loose or watery stools, usually at least three times in 24 hours. It is the consistency rather than the frequency that is important. History Before the 1970s, the agents causing infectious diarrhea were largely unknown in developed countries. It was presumed that viruses were responsible, in contrast to developing countries, where the cause was presumed to be mainly bacterial. The use of electron microscopy to study stool specimens initially from acute diarrhea in adults led to the discovery of the Norwalk agent. Soon thereafter, electron microscopy of small bowel mucosa of children with gastroenteritis in Australia led to the discovery of rotavirus. Rotavirus was soon recognized as the single most common cause of childhood gastroenteritis in developed countries and also a major pathogen in developing countries. Several other viral pathogens such as adenovirus, astrovirus, caliciviruses (including Norwalk agent) have been identified in developed countries but their relative contribution to the disease burden in developing countries largely remains unknown. Progress has been made in the past 20 years in terms of our management of diarrheal disease in both developed and developing countries, which has been evidenced by the fact that in 1980 diarrhea was the leading cause of death for the world's children, accounting for 4,600,000 deaths annually. The last estimate in 1999 for children and adults together was 2,213,000 deaths per year. A major contribution to the fall in mortality was the introduction of oral rehydration therapy in 1979. Table 1 highlights the common bacterial and viral pathogens and the cases per year from data published in 1988 from the Institute of Medicine, National Academy of Sciences, as agents for which new or greatly improved vaccines were needed in the third world, and which could feasibly be developed by 1996. The rotavirus vaccine met this target, as did at least three licensed bacterial vaccines, two live attenuated vaccines (V. cholerae 103 HgR and Salmonella typhi Ty21A) and one killed cholera vaccine. The rotavirus vaccine has subsequently been withdrawn and the efficacy of the bacterial vaccines is not ideal. This table also highlights industry's dependence on the ability to recoup costs for development of these vaccines. Although this situation may be slowly changing, it is still a major issue.TABLE 1: Common bacterial and viral pathogensEpidemiology Developed Countries There is less information on incidence of diarrheal disease in developed countries, probably because it is not perceived as a major cause of mortality but does in fact represent a very large number of consultations and hospitalizations. Table 2 compares the percentage identification of bacterial enteric pathogens in industrialized and developing countries (2).TABLE 2: Percentage identification of bacterial enteric pathogens in symptomatic patients from developing and industrialized countriesChildren younger than 5 years of age each have one to two episodes of diarrhea per year, accounting for 21 to 37 million episodes of diarrhea each year in the United States. This results in 2.1 to 3.7 million consultations and almost 200,000 hospitalizations. It has been estimated that 100 or fewer children under age 5 die of acute diarrheal disease in the United States, but all or nearly all of these deaths are preventable The annual cost of diarrheal disease in the United States is around $1.55 billion per year, and it is estimated that 85% of these costs could be saved with the use of oral rehydration therapy (ORT). Developing Countries Viruses account for up to 40% of cases of severe diarrhea in children in developing countries, in spite of the very large number of episodes of varying severity caused by bacteria. Rotaviruses alone cause 600,000 deaths per year. In Bangladesh, for example, between 15,000 and 27,000 of the 3,000,000 Bangladeshi children born in 1994 would die of rotavirus by the age of 5 (3). Shigella species, campylobacter species, and enterotoxigenic Escherichia coli are the most important bacterial pathogens in developing countries (Table 2). Shigella globally has the highest incidence in children aged 1 to 4 and is the cause of 10% of all diarrheal episodes in children under the age of 5. It results in 250,000,000 cases of diarrhea and about 650,000 deaths annually in developing countries. Campylobacter is hyperendemic in developing countries, found in 8% to 45% of cases of diarrhea and in equal numbers of asymptomatic controls during the first 5 years of life. E. coli are the commonest cause of diarrheal disease in developing countries, and there are at least six types of E. coli enteropathogens. Enteropathogenic E. coli is an important cause of infantile diarrhea in many developing countries. Enterotoxigenic diarrhea (ETEC) together with rotavirus are the leading causes of dehydrating diarrheal disease among weaning infants in the developing world. These children experience two to three episodes of ETEC diarrhea in each of the first 2 years of life, which represents greater than 25% of all diarrheal illness and results in an estimated 700,000 deaths each year. ETEC is also a major cause of travellers diarrhea. Enterohemorrhagic E. coli is now recognized as a global health problem mainly related to the hemorrhagic colitis and hemolytic uremic syndrome that it causes in outbreaks around the world. This has been mainly documented in developed countries, and its effect in developing countries is largely unknown. The major parasitic infections are cryptosporidia and giardiasis, which often have an acute onset but tend to be more chronic in their clinical course. In developed countries, they are most frequently seen in child care centers and nurseries and in homes for the elderly, whereas in developing countries they are endemic and may be a significant contributing factor to persistent enteric disease and malnutrition. This applies particularly to cryptosporidium, which has been shown to be a major contributing factor to malnutrition and ongoing morbidity and mortality in already malnourished children. Other important gut parasites which cause diarrhea include Isospora belli, Strongyloides stercoralis, Trichuris trichuria, and Entamoeba histolytica. They have a variable importance, depending on geographic location and immune status of the child. Pathophysiology Viruses causing enteritis invade mature small intestinal epithelial cells, multiply, cause cell lysis, and then reinvade cells further down the small intestine, leading to total gut infection within 24 hours. The diarrhea is related to the immaturity of cells repopulating the villi. The cells show decreased disaccharidase activity, glucose absorption, glucose-stimulated sodium absorption and decreased basolateral sodium potassium ATPase. Unlike the secretory diarrheas, cyclic AMP and GMP are not increased. Villous blunting decreases luminal surface area. The consequence is a malabsorptive or osmotic diarrhea with a relatively normal stool electrolyte pattern. This process has been shown for rotavirus and is likely to be similar for astrovirus, enteric adenovirus, and calicivirus. It has also recently been reported that a nonstructural rotaviral protein (NSP4) may function as an enterotoxin, but if present, its contribution to diarrhea is probably quite small. Diarrhea caused by bacterial infection is most frequently secretory due to changes in epithelial cell ion transport. Several mechanisms may be at work in this process. After colonization enteric pathogens may adhere to or invade the epithelium, producing either enterotoxins (which elicit secretion by increasing an intracellular second messenger) or cytotoxins. They may also trigger release of cytokines attracting inflammatory cells, which in turn contribute to the activated secretion by inducing the release of agents such as prostaglandins or platelet activating factor. MAJOR ADVANCES Oral Rehydration The major advance so far in the management of diarrheal disease globally has been the use of oral rehydration solutions (ORS) for the treatment of dehydration. In the early 1980s it was thought that all diarrheal episodes should be treated with ORS prepared by dissolving ready-made powders in water. More recently it has been realized that only 30% to 40% of children actually required ORS, and the emphasis has shifted to preventing dehydration using recommended home fluids. It has also been recognized that the amount of fluid given rather than the type of fluid is important, and also the need for continued feeding during diarrheal disease, and the major importance of continuing breast feeding. The most recent estimated regional ORT use rates range from 58% in the Americas to 81% in East Asia and the Pacific, although these figures may be an overestimate (4). Developed countries are belatedly introducing this advance probably also now driven by financial consideration as much as scientific logic (5). Refeeding Refeeding children immediately after rehydration is a major advance that is still to be appropriately and widely implemented (5). This may be one of the main reasons for the demise of protracted post infectious diarrhea and lactase deficiency in developed countries. Prevention Preventive strategies have been much less successful, other than improvements in sanitation and water supplies in developing countries. Viruses have not been dissuaded by these measures and up to 3% of children in developed countries can anticipate hospitalization for viral gastroenteritis before their fifth birthday. Prevention of diarrheal disease either by passive immunization or active immunization has been slow to develop. There is one passive immunity product registered for the prevention of rotavirus infection in children at risk (6). The first commercially marketed rotavirus vaccine has recently been withdrawn because of concerns that immunization was associated with the development of intussusception (7). II. MAJOR ISSUES IN NEED OF INVESTIGATION OR IMPLEMENTATION Implementation of Oral Rehydration Therapy Fluid and nutritional support remain the mainstay of therapy for both viral and bacterial gastroenteritis. Oral rehydration solutions (ORS) designed to replace the acute electrolyte and fluid losses in acute diarrhea are widely available. ORT has been cited in a Lancet editorial as possibly the most significant advance of the 20th century (8), and is recommended globally for the management of acute diarrhea and as shown in Table 3 is the first of the "Nine Pillars of Good Treatment of Acute Gastroenteritis" put forward by the ESPGHAN working group on acute diarrhea (9).TABLE 3: The "nine pillars of good treatment of acute gastroenteritis"Unfortunately, both in developed and developing countries despite the clear recommendations for its use, a most recent WHO assessment is that ORT is being used in less than 50% of the world's episodes of acute diarrhea. A recent survey in Europe on the management of acute gastroenteritis shows that although one in six physicians responding to a questionnaire would not use ORT, 84% would rehydrate over a longer than recommended period and more than 50% would not follow the other seven recommendations (9). In developing countries, the use of ORT has had a significant effect on diarrheal disease mortality over the past 20 years. The estimated annual number of diarrheal deaths of children under age 5 is now equal to one third of the 1980 figure and less than half of the 1990 rate. Further reduction in mortality in developing countries and better implementation of ORT in developed countries will only be obtained if some of the constraints and problems such as those identified below by Guandalini are eliminated (1). These include: Lack of convenience of ORT administration in the practice setting Support staff preference for intravenous therapy. Perceived cost of ORT versus intravenous therapy Lack of training in the emergency room regarding ORT Failure to adequately use nasogastric tube feeding, particularly in the vomiting infant Another major barrier to the adoption of ORS as a therapy has been the fact that it has little effect on symptoms. Vomiting and diarrhea may well continue despite achieving the goal of rehydration, leading users to mistakenly believe that the therapy is a failure. In developing countries, the poor prescription rates of ORS associated with high prescription rates of unnecessary drugs seems to be related to the fact that ORS is not a prestigious drug, "unlike an expensive alternative antibiotic antidiarrheal agent antiemetic or antipyretic (10)." More recently there have been attempts to modify the standard ORS (45–90 mmol sodium: 74–111 mmol glucose). Hyposmolar and rice-based carbohydrate solutions or solutions containing amylase resistant starch (11) have shown improved clinical efficacy in treating cholera with reduced fecal fluid loss and shortened duration of diarrhea. The probiotic lactobacillus rhamnosis strain GG added to ORS has recently been shown in a multi-center European trial to be effective in reducing the severity and duration of diarrhea (12). In summary, there is abundant evidence for the safety and efficacy of ORT but at best it is still only being applied to 50% of episodes of acute diarrhea. There seems to be a major compliance problem, which reflects badly on our ability to "take science where the diarrhea is," as was so elegantly stated by John Rhode in 1976 (13). Immunization Against Diarrheal Disease There is no active immunization available against any viral diarrheal disease except possibly for the prevention of measles, which in developing countries is still a major problem although morbidity and mortality have been reduced by measles immunization. There are several bacterial vaccines available, although their efficacy is generally poor (14). Viral Vaccines The failure of sanitation and clean water in developed countries to prevent viral diarrheal illnesses, particularly rotavirus, highlights the need for an immunization strategy. In January 1999, the American Academy of Pediatrics included for the first time in its recommended immunization schedule three doses of oral rotavirus vaccine to be given at 2, 4, and 6 months of age. Unfortunately, after licensure, reports of intussusception occurring during the 3 to 7 days after dose 1 were received and the tetravalent rotavirus vaccine was withdrawn. Even with a low incidence of intussusception, a scientific case could be made for its use in parts of the world where rotavirus mortality is very high, but moral, legal, ethical, and political factors make this impractical. Second-line candidates are several years away from licensure and other live attenuated virus vaccine candidates will be under suspicion (7). Rare reports of rotavirus antigen in cerebral spinal fluid cause another problem for vaccine production. If in rotavirus it could also with vaccines. and vaccines are also under Rotavirus is as a commercially vaccine of vaccines for other viruses face major have not been so producing attenuated is not little is of the of these other viral agents in developed countries and almost of their in developing countries. The is small for to the large required to a vaccine that has a strategies for vaccine development will be needed on The of vaccines would the of administration and of The of doses to with the best for Vaccines A number of vaccine are for a of the bacterial pathogens and E. These are at of development but not available (14). The available vaccines against cholera and typhi have varying Against Diarrhea Disease there is one commercially available product licensed in Australia for against rotavirus diarrhea in children at This has been shown to be effective in in the and child care centers and in children (6). from by may an less of has also been shown to be effective against and but are commercially available. Refeeding that breast feeding should not be during a of gastroenteritis and that continuing to breast and improved This is particularly important in developing countries where of breast feeding during diarrhea has been shown to have a effect on the development of dehydration. feeding also seems to have a effect against the development of gastroenteritis. In developing countries, the period of risk for infants being breast at the time of weaning because of the of of weaning associated with and immaturity of the immune in the A large by of the published feeding led to the ESPGHAN working group that the management of to children in Europe should of oral rehydration with ORS over 3 to 4 and of normal feeding These are to the developing world. the widely ESPGHAN recommendations for the management and of and the type of a recent survey has shown that children in Europe with acute diarrhea are still being for 24 to (9). This study also that a of responding physicians not follow the of of normal feeding of the after oral The for this could be by either of those relatively new recommendations or their of or to an of normal in children may have nutritional ORS has a effect on by the as a of the improved water and potassium In developed countries, lactase deficiency is but in developing countries in children with a should probably be recommended in the If are a an alternative to and often and relatively protein and for Diarrheal Disease antidiarrheal therapy that was safe, and reduced the amount of stool during a diarrheal illness be a to therapy is not appropriate in the management of gastroenteritis a bacterial cause is because most cases of acute diarrhea are this a recent study from Europe that of physicians would use The use of the cost of may rather than the and the in some infections such as It has been recently shown that treatment of patients with with greatly the risk of developing antibiotic therapy in the for enteric bacterial and pathogens can be as for which therapy is for which therapy is in coli if ETEC on continued to severe diarrhea despite rehydration and campylobacter in in with cell infections in the very if or with These can be by their of of intestinal These agents and with intestinal but not fluid loss and have been associated with and and are not of These agents include which has been shown to a reduction in the duration of diarrhea stool and need for There are concerns about and of water and These agents include or and Although they may the of the they not have significant effect on water of may the absorption of water possibly In a recent European was used in more than of but its has not been well documented and there is scientific suspicion that the duration of diarrhea may of but still the of such agents to or ORS may the of as there is a in the United States with marketed for which many and more with early The use of ORS also which is a factor for their of intestinal can in the treatment of diarrhea the duration of rotaviral and other acute diarrheal illness and prevent diarrheal The improvements have been but in clinical experience with they are likely to a in the treatment of problems related to diarrheal although cost factors probably remain a consideration particularly for developing countries. This has been used to children with diarrhea with rotaviral illness and also in children. This should probably be for children with protracted diarrhea because it is expensive and to be in developing countries. has also been shown to the duration and severity of rotavirus diarrhea in a study from and may be a It should be that some other have to show a in active diarrheal This is an further either in the prevention or in the treatment of acute diarrhea in developing countries particularly in and has been shown to in a in duration and severity of acute onset diarrhea in malnourished children These changes were more in initially and if of be recommended for malnourished children with acute diarrhea. and other have been but large of efficacy are still required to of in Diarrheal Disease In developed countries, the viral pathogens such as enteric and are to as significant causes of diarrheal remains because recently the only available have been electron microscopy and immune electron It is best for outbreaks of diarrheal disease that children and has with increasing frequency as an enteric particularly in both and Other gastroenteritis agents include enteric and The of viral infections other than rotavirus as a cause of diarrheal disease in developing countries is much less although several have shown to be associated with infantile diarrhea in Asia and In the developing world, severe measles infection is often by severe but this has been greatly reduced with the use of the measles vaccine. The major problem in the of enteric viruses is their to be in the and the of such as that could be available. They have been developed for A enteric and More recently have been as important particularly for the which not a common group to bacterial diarrheas, more is being about the enterotoxigenic E. coli and these are of major importance in developing countries. Campylobacter as a cause of enteritis is probably the most important bacterial pathogen in developed countries and is to be as a major cause of diarrhea in developing countries (Table 2). Other agents that have been around for some time such as and have only recently been associated with is less frequently in developed countries but in developing countries, particularly Bangladesh, it represents the leading cause of bacterial gastroenteritis. The of in Diarrheal Disease infections have a high in of the world, mainly in the and cause morbidity and a major on child and need to be as one of the of any diarrhea the small some the large intestine, and several such as and can both The major parasites causing significant diarrhea include Entamoeba Isospora belli, Trichuris and Strongyloides can have a of up to 30% in developing countries in children. It may be and its contribution to disease in developing countries particularly malnutrition and is largely unknown. at of in children in developing countries to nutritional status have not shown evidence of is by water or to and is an important cause of diarrheal disease in malnourished children as well as a major problem in the particularly with It is also an important cause of diarrhea in child care There is at no effective agent for Implementation of Oral Rehydration Therapy More data are required about to its use in both developed and developing countries. A survey similar to that recently in Europe could be globally by WHO and with the support of the world's It is from the European study that more are required to the of or to recommendations for management of acute diarrhea. This has to be at all of care from and to of this the of nasogastric feeding in the management of children with acute diarrhea to be The use of a single ORS for all diarrheal illness and has been by results from two recently published well clinical Further are still required in Asia and also in developed countries. The of or such as to be These are global and in the of measures or active immunization they as much support as other The and and other about child health should be for in both developed and developing countries would be needed to support the use of new Immunization Against Diarrheal Disease development should be a major in the global to diarrheal disease in children and This significant should be made to development and of vaccines so that they would be appropriate and for developing The will be a major in vaccine A to which agents of diarrheal disease vaccine a that be made on and one that at be made for the of appropriate particularly in developing countries. This is another for the world's Refeeding In both developed and developing countries, the of breast feeding still emphasis because it a with low and and and cost are also significant reasons to continue breast feeding. This has been for many years by and other bodies in both developed and developing countries in support of child health but it would be appropriate for the world bodies of and to this and if a This may be important in developed countries where breast feeding is More to be regarding management of acute diarrhea in both developed and particularly developing countries. diarrhea is still a major that in may be due to the acute gastroenteritis is The is already there and to is the development of in each by the and health bodies as well as WHO and to the information so that it at all and particularly and in the It has to be a in developing countries. and for Diarrheal Disease significant evidence to the particularly and to a and are still widely used in the treatment of acute diarrheal disease in children. This situation highlights the need for more in both developed and developing countries and also the development of a to the against and information on the use of these agents for diarrheal disease in children. for the use of in diarrheal disease also need to be and to both developed and developing countries. The continued use of is already leading to the of resistant against such as and of a to at available for the management of diarrheal disease in both developed and developing countries is best under a global such as or more appropriately a the world's and to In a similar recommendations could be put forward to the in the management of diarrheal disease such as the of to oral rehydration therapy and their use in management of diarrheal disease the of passive immunity and also the use of of in Diarrheal Disease The of many of the pathogens in terms of importance of diarrheal disease and malnutrition in both developed and developing countries is largely unknown. This is mainly related to the of and also in which to If are to better the global of diarrheal disease and relative importance of viruses and parasites as need to be in developing countries that are with the appropriate to the of the from both an and a clinical This to be under the of WHO and but also could both bodies and by a from the world's The of in Diarrhea Disease The importance of parasitic infections as a cause of diarrheal disease in both developed and developing countries is to because of of global of in many countries will of data by a such as and would information on and of and effective for these infections should also be